Encapsulated time release pellets and method for encapsulating the same



United States Patent Massachusetts No Drawing. Filed June 26, 1961, Ser.No. 119,269 20 Claims. (Cl. 167-83) The present invention relates to anovel method of encapsulating solid medicinal pellets, pills or beadletsfrom which the medicinal material is released at a predetermined rateover a predetermined delayed time interval when the pellets are takeninternally. Such pellets are conventional and are referred to herein astime release pellets. The invention also relates to the novelencapsulated time release pellets made in accordance with such methodand to a novel intermediate form in which the pellets are placed inorder to so encapsulate them.

The controlled rate of release of the medicinal is achieved byformulating the time release pellets so that when taken internally theouter layers thereof disintegrate at a controlled rate to therebyrelease the medicinal at the desired rate over an extended period oftime. While time release pellets are commercially available, and henceper se form no part of this invention, they may be described asconsisting of a pellet nucleus built up from a head of sugar coated withsucessive layers or coatings of sucrose or simple syrup and alternatelayers of starch, to which the medicinal is commonly applied as a powderto a liquid coating of simple syrup during a suitable tumbling processand over which a coating of wax is applied which serves to retard thedisintegration of the coating containing the medicinal. The wax coatingmay conveniently consist of castor wax formulated from hydrogenatedcastor oil. By selection of medicinal formulations and thicknesses ofthe medicinal and wax coatings, the rate of release of medicinal fromthe pellet can be controlled and delayed in a predictable manner.

By varying the make up of different pellets, e.g. the thicknesses of thecoatings, the formulation of the medicinal, etc., their rate of releaseand delay can be varied. By admixing together a number of thesedifferent pellets having different release rate and time delaycharacteristics the medicinal can be released at a controlled rate overa relatively long time interval. For example, the medicinal will bereleased from one group of pellets over a certain time interval followedby release of medicinal from another group of pellets over a succeedingtime interval so that the medicinal will be released at a predeterminedrate to maintain the desired blood level of the medicinal over arelatively long total time interval. Such an admixture of pellets havingdifferent release rate and time delay characteristics typically includessome pellets on' which the wax coating over the medicant coating isomitted entirely so that the period of sustained theropeutic activitycommences promptly after a capsule containing the admixture of timerelease pellets is ad ministered to a patient. In this manner, apredictable, even, smooth, continuous level of therapeutic activity canbe achieved over a period of as long as twelve hours or more with nosudden, abrupt rises in blood levels, no dumping and noup-hill-down-dale effects, as is so often the case with enteric-coatedtablets, repeat-action tablets and other substained action medications.Furthermore, patients are not as likely to interrupt therapy or missdosage because of forgotten administration since the number of dosagesmay be reduced.

Each dosage of time release pellets requires a relatively largepredetermined quantity of pellets (conventional pellets may vary widelyin size over a wide range which typically includes sizes from theopening size of 3,139,383 Patented June 30, 1964 a 10 mesh standardscreen to the opening size of a 40 mesh screen). In the past, suchpredetermined quantities of pellets have been encapsulated in a drystate in hard shelled, two piece capsules. However, such capsules havethe disadvantage that they may be tampered with, which can result in aloss or removal of pellets to thereby decrease the dosage below thatrequired. Furthermore, these capsules are not hermetically sealedagainst air and moisture which in many instances are detrimental to thepellets. Since the pellets are encapsulated in a dry state theirsurfaces are exposed to moisture and air. Also collision of the drypellets with each other and with the handling equipment during handling,e.g. during encapsulation, may result in damage to the carefullyformulated surface coatings which alters the time releasecharacteristics of the pellets.

Accordingly, it is an object of the present invention to provide amethod of encapsulating time release pellets in hermetically sealed,tamper-proof capsules in which the surfaces of the pellets are protectedfrom exposure to air and moisture and are protected against damage dueto collision during handling.

Although, certain medicinals, such as vitamins, have been encapsulatedin hermetically sealed, soft shell (gelatin) capsules, in order to do soautomatically with pressently existing machinery such as that describedin US. Patents Nos. 2,549,327 and 2,638,052 the medicinal must be in theform of a liquid or a paste which demonstrates fluidity under theparticular feed system employed, that is a gravity feed or a pressurefeed. Otherwise it cannot be accurately metered and pumped by themetering valve and pump mechanism (US. Patent No. 2,638,052) of suchmachinery, which mechanism automatically meters out and loads a measureddosage into the capsules. The capsules are formed, loaded andhermetically sealed automatically by the machine.

In order to provide the desired dosage, the medicinal or medicant in arelatively concentrated form is commonly suspended in a conventionalpharmaceutical carrier such as corn oil, cotton seed oil, or some othervegetable oil or the like so that the quantity of the resulting mixturerequired to fill a capsule will contain the desired dosage. It isessential that the medicant be uniformly suspended in the carrier andthat the suspension be stable so that the medicant will remain uniformlydistributed in the carrier at the time of loading in order for themeasured dosages (measured by volume or weight) loaded into the capsulesto contain a predictable uniform quantity of medicant. Consequently, ifthe medicinal or medicant is originally in the form of a solid, it mustfirst be ground into a fine powder as by a ball milling operation inorder to provide the required stable uniform suspension. In such case,the carrier functions to place the solid medicant in a form which can behandled by the metering and pumping mechanism and also functions as adiluent.

A serious problem which has prevented the use of this encapsulatingtechnique to encapsulate the above-mentioned time release pellets istheir relatively large sizes (as aforesaid, conventional batches usuallyinclude sizes which are substantially larger than the opening size of a40 mesh screen) as compared to the finely ground powders conventionallyused with such techniques. Such large sizes are required in order toachieve the time release characteristics referred to above. On one hand,the pellets are too large to be uniformly distributed in a stable liquidsuspension using conventional pharmaceutical liquid carriers. On theother hand, the pellets cannot be ground to a powder fine enough foruniform stable suspension in conventional pharmaceutical liquid carrierswithout destroying their predetermined and predictable time releasecharacteristics. Finally, since the pellets 3 in their dry state do notdemonstrate all of the fluid properties necessary for successfulencapsulation in soft shell capsules using the metering valve and pumpmechanism referred to above on the machinery referred to above, thesepellets cannot be encapsulated in their dry state with presentlyexisting machinery.

Accordingly, it is another object of the invention to encapsulatepredictable and substantially uniform (within acceptable limits) dosagesof such time release pellets in soft shell, hermetically sealed capsulesutilizing the above-mentioned known encapsulating techniques and withoutreducing the size of the pellets, whereby the time releasecharacteristics thereof are preserved. This is achieved by metering andloading the pellets in the form of a novel, stable liquid suspension inwhich the pellets remain uniformly dispersed for a long period of timeunder normal environmental conditions (including normal storage andencapsulation conditions) and which can be easily handled by themetering and pumping mechanism. This insures that the metered dosagesloaded into the capsules by such mechanism will contain substantiallyuniform quantities of pellets even when the suspension is stored for asubstantial period of time before encapsulation. The liquid suspensionis formed by suspending the pellets in a novel liquid carrier which notonly places the pellets in a form in which they can be successfullyutilized with the above-mentioned conventional equipment but alsoprotects the pellets against contact with air or moisture and againstdamage to their surfaces due to collision during handling.

A number of serious problems had to be overcome in order to do this. Themajor problem, of course, was to find a way of forming a stable uniformliquid suspension of such large particles. This problem was complicatedby the fact the suspension could not contain anything which wouldunpredictably interfere with the time release characteristics of thepellets. This ruled out the use of most dispersing agents which functionas such by collecting, presumably in the form of a coating, on thesurfaces of the pellets to thereby alter the surface tension conditionsat the interfaces of the carrier and the pellets. Such a coating wouldinterfere with the time release characteristics of the pellets.Furthermore, a carrier could not be used in which the pellets were atall soluble because this would cause the pellet coatings to dissolve tothereby destroy the time release characteristics of the pellets. It wasessential that the carrier and its contents (other than the pellets) beinert with respectto the pellets and to the gelatin capsule materialwhich ruled out glycerine and water (water would dissolve the carefullyformulated water soluble pellet coatings and glycerine would soften thegelatin capsule material) and wax solvents. Also, it was essential thatthe carrier and its contents be non-toxic, which ruled out many wellknown carriers and dispersing agents, and that it be sufiicientlyflowable with the pellets suspended therein and at the temperatures(usually 72 F.) at which hermetically sealed, soft shell capsules areusually manufactured so as to be readily handled by the metering andpumping mechanism.

Accordingly, it is another object of the present inven tion to provide astable, uniform liquid suspension of the above-mentioned time releasepellets in a carrier without reducing their size and withoutunpredictably changing the time release characteristics of the pellets,such carrier being inert with respect to the pellets and capsule,nontoxic and sufiiciently fiowable with the pellets suspended therein tobe readily handled by the metering and pump ing mechanism. This isachieved by suspending the pellets in a thick, viscous carriersufi'iciently viscous to hold the pellets in stable, uniform suspensionfor a relatively long period of time under normal environmentalconditions (including normal storage and encapsulation conditions) butsufficiently flowable to be readily handled by the metering and loadingmechanism. The carrier is preferably formulated by blending a compoundwhich is normally liquid at room temperature with a compatiblethickening compound which is normally solid at room temperature toprovide a thick, viscous, homogeneous carrier blend, the thickener beingadded in an amount sufficient to provide the blend with the desiredviscosity.

A serious problem which arose with the use of such a viscous carrier wasthat the viscosity required to provide a stable suspension is so highthat it is difficult to uniformly mix and disperse the pellets in thecarrier, which is necessary in order that the dosages metered out andloaded by the aforementioned metering and pumping mechanism containsubstantially uniform and predictable quantities of pellets.

Accordingly, it is another object of the invention to provide a carrierof the type described above having the desired high viscosity to achievea stable uniform suspension of the time release pellets but in which thepellets can be easily and uniformly dispersed. This is achieved byemploying a carrier which has a high viscosity at normal temperatures,including encapsulating temperatures, but the viscosity of which issharply reduced to a value at which the pellets are easily admixed anduniformly dispersed therein when the temperature thereof is in creased,the pellets being mixed and dispersed in the carrier while it is at suchelevated temperature.

However, another problem was introduced because the pellets cannot beraised above a relatively low elevated temperature, about 122 F.,without 'detrimentally affecting the pellets. One Way in which thepellets are detri mentally affected is that the wax outer coating ismelted.

Accordingly, it is yet another object of the invention to provide acarrier which has the desired high viscosity at encapsulatingtemperature but the viscosity of which is sharply reduced to arelatively low viscosity at which the pellets are easily disperseduniformly therein by increasing the temperature thereof to a relativelylow elevated temperature below the temperature at which the pellets areadversely affected. This is achieved by the use of a carrier comprisinga polymerized alkylene glycol, including alkoxy polyalkylene glycols(e.g. methoxy), which is liquid at room temperature and which isthickened to the desired viscosity with a polymerized alkylene glycol,including alkoxy polyalkylene glycols (e.g. methoxy), which is solid atroom temperature and which has a greater molecular weight than saidfirst-mentioned polym'erized alkylene glycol. Liquid and solidpolymerized ethylene glycols are preferred although polypropyleneglycols are also satisfactory.

Preferred carriers are normally liquid polymerized polyethylene glycolshaving approximate average molec ular weights ranging from about 190 to630 and Saybolt viscosities at 210 F., sec., from about 38 to 66 andwhich are sold by Carbide and Carbon Chemicals Company unde'rthe tradenames Polyethylene Glycol 200 to 600, thickened with more highlypolymerized, normally solid polyethylene glycols, which have approximateaverage molecular weights between about 950 and 7500 and Say boltviscosities at 210 R, see, from about to 4200 and which are sold byCarbide and Carbon Chemicals Company under trade names CarbowaxCompounds 1000 to 6000. A preferred liquid polyethylene glycol is onehaving an approximate average molecular weight of about 380-420 and aSaybolt viscosity at 210 F., sec., from about 45 to 55 and which is soldby Carbide and Carbon Chemicals Company under the trade namePolyethylene Glycol 400. A preferred solid polyethylene glycol is onehaving an approximate average molecular weight of about 3000-3700 and aSaybolt viscosity at 210 F, sec., of from about 350 to 400 and which issold by Carbide and Carbon Chemicals Company under the trade nameCarbowax Compound 4000.

A polyglycol carrier blend having a viscosity of at least 1000centipoises measured with a standard Brookfield SynchroelectricViscometer Model LVF at a temperature of 72 F. (spindle number 4 and aspindle speed of 60 r.p.m.) is preferred to keep the pellets in uniformsuspension although the minimum viscosity of the carrier will depend onthe size of the pellets. Such minimum viscosity will be greater withgreater particle sizes.

The maximum viscosity of the carrier is dictated only by the maximumviscosity of the suspension of the pellets in the carrier which can behandled satisfactorily by the metering and pumping mechanism at normalencapsulating temperatures (between about 70 F. and 90 F.), whichtemperatures closely approximate room temperature (an encapsulatingtemperature which is commonly used is 72 F.) with the particular feedsystem employed.

Since the viscosity of the carrier is increased by increasing theproportion of solid polyglycol to liquid polyglycol, the proper minimumviscosity for any particular particle size can be readily ascertained byincreasing or decreasing such proportion until the desired stability ofthe suspension for that particle size is achieved. A satisfactorycarrier viscosity is obtained for a range of pellet sizes passingthrough a 20 standard mesh screen but being retained on a 25 sttandardmesh screen where the amount of solid polyglycol is between about 8% and13% by weight of the carrier, the rest of the carrier comprising theliquid polyglycol.

Although the maximum amount of thickener is dictated only by the maximumviscosity of the suspension which can be handled by the above-mentionedconventional metering and pumping mechanism, it is uneconomical for anumber of reasons to increase the carrier viscosity beyond what isrequired for a stable suspension. Examples of such reasons are theincreased difficulty in handling the suspension and the increaseddifficulty in physically mixing the pellets into the carrier. Theminimum amount of thickener of course, depends on the minimum carrierviscosity as described above. However, the lower the molecule weight ofeither or both of the solid and the liquid polyglycol, the greater theproportion of solid polyglycol to liquid polyglycol which is necessaryto obtain the same minimum carrier viscosity.

The proportion of pellets in the suspension is not particularly criticaland may range from about to 30% by weight, the remainder of thesuspension comprising the carrier. However, a range of from 15% to 25%by weight is preferred. The proportion of pellets in any particularsuspension will depend on the pellet dosage (quantity of pellets)desired per capsule to provide the required amount of medicant percapsule. Thus, for any given capsule volume, a proportion of pellets isselected to provide the desired quantity of pellets in that volume. EX-cept for this requirement there is no minimum proportion of pellets. Themaximum proportion is dictated only by the fact that the proportion ofpellets to carrier should not be so great that the suspension becomestoo stifi to be efliciently handled by the metering and loadingmechamsm.

An important advantage of the blended polyglycol carriers of the presentinvention is that although at normal room temperatures, which includenormal storage and encapsulating temperatures, the carrier issufiiciently thick and viscous to hold the pellets in stable suspension,at elevated temperatures below the maximum temperature to which thepellets can be exposed without detrimental etfect but well above normalstorage and encapsulating temperatures, the viscosity thereof is reducedsubstantially to a relatively low value at which the pellets can beeasily mixed and dispersed uniformly therein. It has been found thatwhen the solid and liquid polyglycol blend is heated from roomtemperature there is a sudden and substantial drop in viscosity as theblend is heated through a relatively narrow transition temperaturerange. This transition temperature range at which the sudden drop inviscosity occurs is below the maximum temperature (122 F.) to which thepellets can be exposed and Well above normal storage and encapsulatingtemperatures and depends on the amount of the solid polyglycol which ispresent, the greater the amount of such solid polyglycol, the higher thetemperature at which the sudden drop occurs. For example, with a carrierblend containing 12% solid Carbowax Compound 4000 and 88% liquidPolyethylene Glycol 400 the viscosity drops from 5 640 cps.(centi-poises using Brookfield Synchroelectric Viscometer Model LVF withspindle No. 4 and a spindle speed of 60 rpm.) at 72 F. to 50 cps.(centipoises using Broo-kfield Viscometer with spindle No. 1 and aspindle speed of 60 rpm.) at F., most of this drop in viscosityoccurring in the transition temperature range between about 1l6.6 F. and120.0 F., and with a carrier formulation of 9% solid Carbowax Compound4000 and 91% liquid Polyethylene Glycol 400 (using the same viscositymeasuring technique and apparatus used with the 12% solid polyglycolblend) the viscosity drops from 1340 cps. at 72 F. to 46 cps. at 120 F.,the major portion of this drop occurring in the transition temperaturerange between about 113.0 F. and ll8.4 F. This sudden drop in viscosityoccurring in the transition temperature range is accompanied by theblend changing from a thick, viscous opaque state to a thin, fluidtransparent state.

It has also been found that when the heated polyglycol blend is cooledthe viscosity increases sharply and suddenly within a lower transitiontemperature range (as compared to the transition temperature rangeduring heating) which is about the same regardless of the relativeproportions of solid and liquid polyglycol. Thus, with Carbowax Compound4000 and Polyethylene Glycol 400 when the temperature is reduced thesudden and substantial increase in viscosity occurs between 105.8 F. and98.6 F. This sudden increase in viscosity is again accompanied by theblend changing from a thin, fluid transparent state to a thick, viscousopaque state and, as aforesaid, is the same regardless of the relativeproportions of solid polyglycol and liquid polyglycol.

The liquid and solid polyglycol blend is preferably formulated by mixingthe solid polyglycol into the liquid polyglycol with agitation at atemperature above or at the melting temperature of the solid polyglycol.Such melting temperature for Carbowax Compound 4000 is between about 127F. and 133 F. However, it is different for other solid polyglycols. Forexample, the melting temperature of Carbowax Compound 1000 is between98.6 F. and 104 F. The maximum temperature at which the solid polyglycolcan be added to the liquid polyglycol is dictated only by economics andthe maximum temperature to which the polyglycols can be subjectedwithout detrimental effect. From an economic standpoint it is desirableto add the solid polyglycol to the liquid polyglycol at the lowesttemperature at which the solid polyglycol melts rapidly and is blendedwith the liquid polyglycol into a homogeneous liquid of low viscosity.Good results are obtained with a blend of Carbowax Compound 4000 andPolyethylene Glycol 400 when the solid polyglycol is added to the liquidpolyglycol at F. The Brookfield viscosity of such blend at thattemperature with 9% solid polyglycol and 91% liquid polyglycol is 31cps. and with 12% solid polyglycol and 88% liquid polyglycol it is 35cps., both viscosities being measured at 60 r.p.m. with spindle No. 1.

This elevated temperature required for mixing the solid CarbowaxCompound 4000 with the liquid Polyethylene Glycol 400 to obtain thecarrier blend is too high for the pellets. Consequently, after the twopolyglycols have been admixed and before the pellets are added to thecarrier blend the temperature of the blend is reduced to a temperatureat or below the maximum temperature (122 F.) to which the pellets can besubjected without detrimental effects but above the transitiontemperature range at which the viscosity of the blend increases sharplyas aforesaid. One such temperature which has been found satisfactory forthis particular blend is 120 F. The pellets are added to the blend atthis lower elevated temperature at which the viscosity is stillrelatively low and are uniformly mixed and dispersed throughout thecarrier by agitation with a mixer. Thereafter, the blend is cooled whilestill being mixed, to thereby keep the pellets in suspension, throughthe transition temperature range, at which the viscosity increasessharply, to room temperature at which the suspension is highly viscousand the pellets remain suspended uniformly in the carrier for longperiods of time without mixing. Of course, where the melting temperatureof the solid polyglycol is below the maximum temperature to which thepellets can be safely exposed it may not be necessary to reduce thetemperature before adding the pellets.

After cooling, the stable, viscous suspension of pellets can be storedbefore being encapsulated in hermetically sealed, soft shell capsuleswith the apparatus disclosed in the above-mentioned patents, or it canbe so encapsulated immediately. In either case, the time release pelletsremain uniformly suspended in the carrier so that there is a predictableuniform quantity of pellets in each dosage automatically loaded into thepellets by the metering and pumping mechanism. Furthermore, although thesuspension is thick and viscous it is suificiently flowable so that itcan be readily handled by the metering and pumping mechanism.

As aforesaid, the size of the time release pellets, which areconventional and available on the market, vary over a wide range ofsizes which typically includes pellet sizes ranging from a sizecorresponding to the opening size of a 10 mesh screen to a sizecorresponding to the openmg size of a 40 mesh screen. However, inaccordance with the present invention, it is preferable to utilizepellets which are generally uniform in size, e.g. sufiiciently uniformso that the difference in the sizes of a screen on which they are heldand a screen through which they pass is not much greater than aboutmesh. Pellets of generally uniform sizes can be obtained by screeningconventlonal batches of time release pellets or by screening a batch ofpellets before the coating of medicinal is applied followed by againscreening the finished coated pellets.

The highly viscous carrier not only holds the pellets in uniformsuspension, thereby placing them in a form in which they can be usedwith conventional techniques for encapsulation in hermetically sealed,soft shell capsules, but also protects their surfaces from becomingdamaged and their shape from being changed by collision with each otherand with the handling equipment during handling, e.g. during meteringand loading. This is of extreme importance because any damage to thesurfaces or any change in shape will damage the coatings that initiallywere carefully manufactured for the express purpose of potency controlin the rate of medication release. The

viscous carrier also protects such coatings from contact with moistureand air.

Example I 31.68 lbs. of liquid Polyethylene Glycol 400 sold under thatname by Carbide and Carbon Chemicals Company was heated to 140 F. 4.32lbs. of solid polyethylene glycol sold under the trade name CarbowaxCompound 4000 by Carbide and Carbon Chemicals Company was blended intothe heated liquid polyglycol by stirring with a stirrer having a 5"blade and rotating at an rpm. of 170 r.p.m. which was slow enough toavoid Whipping any substantial amount of air into the mix. The mixturewas mixed for one hour at 140 F. during which the solid polyglycolmelted and was uniformly dispersed in the liquid polyglycol to form 36lbs. of a thin, transparent homogeneous liquid made up of 12% solidpolyglycol and 88% liquid polyglycol and having a Brookfield viscosityat 140 F. (spindle No. 1 and spindle speed of 60 r.p.m.) of 35 cps.(centipoises). The resulting homogeneous blend or carrier was allowed tocool to 120 F.

(below the maximum temperature-122 F.-to which the pellets can be safelyexposed) at which temperature F.) it had a Brookfield viscosity of 50cps. (spindle No. 1 and spindle speed of 60 r.p.m.) and was still thinand transparent. Nine lbs. of a batch of conventional time releasepellets (sometimes referred to as timed disintegration pellets) havingd-amphetamine sulfate medicant coatings over sugar, sucrose and starchbases with wax coatings over the medicant and of a size passing througha 20 mesh standard screen but not through a 25 mesh standard screen (thepellets before being coated with medicant and wax passed through a 30mesh screen but not through a 35 mesh screen) were added to the carrierat 120 F. while it was being agitated by the stirrer rotating at rpm.The carrier was held at this temperature with continued stirring untilthe pellets were dispersed uniformly throughout the carrier, whereafterthe suspension was cooled to 72 F. with continued stirring. Duringcooling the viscosity of the carrier blend sharply increased over atransition temperature range of from 105.8 F. to 986 F. During suchtransition period the carrier blend changed from a relatively freeflowing, thin transparent state to a thick, highly viscous, opaquestate. At 72 F. (room temperature) the Brookfield viscosity (spindle No.4 and spindle speed of 60 rpm.) of the carrier blend was 5640 cps., themajor portion of the increase in viscosity from 120 F. to 72 takingplace in the above-mentioned transition temperature range. Thesuspension at 72 F. was very thick and viscous but flowable. It wasopaque and and contained 20% by weight of pellets and 80% by weight ofcarrier. The pellets remained uniformly suspended with no perceptiblesettling for a number of days. It was noted that upon heating thecarrier it decreased sharply in viscosity in a transition temperaturerange of between 116.6 F. and 120.2 F. below the maximum temperature(122 F.) to which the pellets can be subjected. The suspension wasencapsulated at 72 F. in soft shell, hermetically sealed gelationcapsules in a conventional encapsulating machine of the type describedin U.S. Patent No. 2,549,327 and having a metering valve and pump of thetype described in U.S. Patent No. 2,63 8,052 with a gravity feed andwithout concurrent agitation of the suspension. The metering valve andpump satisfactorily and accurately metered and loaded the suspension inthe capsules without harming the surfaces or shape of the pellets andthe pellets remained uniformly suspended in the suspension throughoutthe operation so that each load or dosage metered and loaded into eachcapsule contained a substantially uniform and predictable quantity ofpellets (within acceptable limits of uniformity).

The pellets were formulated and mixed by the manufacturer as inconventional practice to achieve a predetermined rate of release of thed-amphetamine sulfate medicant (useful for the control of appetite inweight reduction and for the treatment of depressive states andalcoholism) of about 30-40% of the total medicant after one hour, 50-60%after two hours, 70-80% after five hours and 80-90% after eight hours.The average medicant content of the pellets was 114.8 mg. per gram ofpellets and the medicant dosage per capsule was 15 milligrams.

By conventional testing procedure, the release rate of the medicant inthe encapsulated suspension of this example was as follows:

Percent 1 hour 36.6 2 hours 58.7 5 hours 79.1 8 hours 82.0

A number of these encapsulated pellets were satisfactorily administeredto a number of patients with positive results and with no ill effects.

These results showed that the time release characteristics of thepellets were not altered by the encapsulation satisfactory.

Example II Example H was the same as Example I except that the solidpolyglycol comprised 9% of the carrier and the liquid polyglycolcomprised 91%. The carrier blend had a Brookfield viscosity of 31 cps.at 140 F. and 46 cps. at 120 F. (spindle No. 1 and spindle speed of 60r.p.m.). The carrier had a Brookfield viscosity of 1340 cps. at 72 F.(spindle N0. 4 and spindle speed of 60 rpm). The transition temperaturerange at which the viscosity of the carrier blend increased sharplyduring cooling was the same as in Example I. However, the transitiontemperature range of the carrier during heating was between 113.0 F. and118.4 F.

Other embodiments of the invention will become apparent from thepreceding description, it being understood that such description,especially the specific examples, are only illustrative and that theinvention is not limited thereto or thereby but only by the claimshereof and their equivalents.

I claim:

1. An encapsulated, stable liquid suspension of time release medicinalpellets having a predetermined rate of medicinal release over apredetermined delayed time interval, said pellets being dispersed andsuspended in a substantially moisture-free, thick, viscous but flowableliquid carrier in which said pellets are substantially insoluble, saidsuspension being encapsulated in a soft shell, hermetically sealedcapsule, said carrier being inert with respect to said pellets and saidcapsule and comprising a homogeneous blend of a non-toxic compound whichis liquid at room temperature and a non-toxic thickening compound whichis solid at room temperature and which is present in an amount to renderthe carrier sufiiciently viscous to hold said pellets in suspension,said carrier being substantially inert with respect to effect on saidpredetermined rate of medicinal release of said pellets.

2. A stable, liquid suspension of time release medicinal pellets havinga predetermined rate of medicinal release over a predetermined delayedtime interval, said pellets being dispersed and suspended in asubstantially moisture-free, thick, viscous but flowable liquid carrierin which said pellets are substantially insoluble, said carrier beinginert with respect to said pellets and comprising a homogeneous blend ofa non-toxic compound which is liquid at room temperature and a non-toxicthickening compound which is solid at room temperature and which ispresent in an amount to render the carrier sufficiently viscous to holdsaid pellets in stable suspension, said carrier being substantiallyinert with respect to effect on said predetermined rate of medicinalrelease of said pellets.

3. An encapsulated, stable liquid suspension of time release medicinalpellets having a predetermined rate of medicinal release over apredetermined delayed time interval, said pellets being dispersed andsuspended in a thick, viscous but flowable liquid carrier in which saidpellets are substantially insoluble, said suspension being encapsulatedin a soft shell, hermetically sealed capsule, said carrier comprising ablend of a polyalkylene glycol which is liquid at room temperature and ahigher molecular weight polyalkylene glycol which is solid at roomtemperature, said solid polyethylene glycol being present in an amountto render said carrier sufliciently viscous to hold said pellets insuspension in said carrier.

4. An encapsulated suspension according to claim 3, said solid andliquid polyalkylene glycols comprising polyethylene glycols, said liquidpolyethylene glycol having an average molecular weight between about 190and 630 and having a Saybolt viscosity at 210 F., sec., ranging fromabout 38 to 66, said solid polyethylene glycol having an averagemolecular weight between about 950 and 7500 and a Saybolt viscosity at210 F., sec., ranging from about 85 to 4200.

5. An encapsulated suspension according to claim 3, the Brookfieldviscosity of said carrier being at least 1000 centipoises at 72 F. usingspindle No. 4 and with a spindle speed of 60 r.p.m., said pellets beinglarger than the opening size of a 40 mesh screen.

6. A stable liquid suspension of time release medicinal pellets having apredetermined rate of medicinal release over a predetermined delayedtime interval, said pellets being dispersed and suspended in a thick,viscous but flowable carrier comprising a blend of a normally liquidpolyalkylene glycol and a normally solid polyalkylene glycol of greatermolecular weight than said liquid polyalkylene glycol. 7. A stableliquid suspension according to claim 6, said polyalkylene glycolscomprising polyethylene glycols, said liquid polyethylene glycol havingan average molecular weight between about 380 and 420 and a Sayboltviscosity at 210 F., sec., ranging from about 45 to 55, said solidpolyethylene glycol having an average molecular weight between about3000 and 3700 and a Saybolt viscosity at 210 F., sec., ranging fromabout 350 to 400. 8. A method of encapsulating in soft shellhermetically sealed capsules discreet medicinal pellets having apredetermined rate of medicinal release over a predetermined delayedtime interval by virtue of the construction of the pellets withoutinterfering with said rate of release, said method comprisinghomogeneously blending together a non-toxic compound which is liquid atroom temperature with a non-toxic thickening compound which is solid atroom temperature to provide a carrier which is highly viscous butreadily flowable under normal storage and encapsulation conditions andin which said pellets are insoluble, mixing said pellets into saidcarrier with agitation to thoroughly disperse and suspend said pelletsin said carrier, said solid compound being present in a quantity torender said carrier sufficiently viscous under normal storage andencapsulating conditions to hold said pellets in stable suspension, andencapsulating the resulting suspension in a soft shell hermeticallysealed capsule, said carrier being substantilly inert with respect tosaid pellets and said capsule material and with respect to predictablerate of medicinal release of said pellets.

9. A method of encapsulating medicinal pellets having a predeterminedrate of medicinal release over a predetermined delayed time interval,said method comprising forming a homogeneous blend of a non-toxiccompound which is liquid at room temperature and a non-toxic compoundwhich is solid at room temperature, mixing said pellets in said blend atan elevated temperature and with agitation to disperse said pellets insaid blend, said blend having a substantially lower viscosity over arange of higher temperatures including said elevated temperature thanover a lower range of temperatures, said blend containing an amount ofsolid compound to render the blend sufiiciently viscous at said lowertemperature range to hold said pellets in suspension, reducing saidelevated temperature of said suspension to a lower temperature withinsaid lower range to thereby increase its viscosity said elevatedtemperature being not greater than the maximum temperature which saidpellets can withstand without deleterious effects, and encapsulatingsaid suspension in a soft shelled hermetically sealed capsule at atemperature within said lower range, said suspension being agitatedwhile it is cooled from said first elevated temperature to said lowertemperature.

10. A method of encapsulating medicinal pellets having a predeterminedrate of medicinal release over a predetermined delayed time interval,said method comprising forming a homogeneous blend of a polyalkyleneglycol which is liquid at room temperature and a polyalkylene glycol ofgreater molecular weight than said liquid polyalkylene glycol and whichis solid at room temperature, mixing said pellets in said blend at anelevated temperature and with agitation to disperse said pellets in saidblend, said blend having a substantially lower viscosity over a range ofhigher temperatures including said elevated temperature than over alower range of temperatures, said blend containing an amount of solidpolyalkylene glycol to render the blend sufiiciently viscous at saldlower temperature range to hold said pellets in suspension, reducingsaid elevated temperature of said suspension to a lower temperaturewithin said lower range to thereby increase its viscosity, said elevatedtemperature being not greater than the maximum temperature which saidpellets can withstand without deleterious effects, and encapsulatingsaid suspension in a soft shell hermetically sealed capsule at atemperature within said lower range.

11. A method according to claim 10, said solid and liquid polyglycolsbeing mixed at a second elevated temperature higher than said firstelevated temperature, said second elevated temperature being at leastthe melting temperature of said solid ,polyalkylene glycol and beingwithin said higher range, whereby said solid polyalkylene glycol ismelted and dispersed in said liquid polyalkylene glycol in a meltedstate to form said homogeneous blend, said method including reducing thetemperature from said second elevated temperature to said first elevatedtemperature and thereafter adding said pellets at said first elevatedtemperature, said suspension being agitated while it is cooled from saidfirst elevated temperature to said lower temperature.

12. A method according to claim 10, said pellets being of a size passingthrough a screen of one size and being retained on a screen of a sizewhich is about mesh greater than said screen of said one size.

'13. A method according to claim 10, said polyalkylene glycolscomprising polyethylene glycols.

14. A method according to claim 13, said liquid polyethylene glycolhaving an average molecular weight between about 190 and 630 and aSaybolt viscosity at 210 F., sec., ranging from about 38 to 66 and saidsolid polyethylene glycol having an average molecular weight betweenabout 950 and 7500 and a Saybolt viscosity at 210 F., sec., ranging fromabout 85 to 4200.

15. A method according to claim 13, said blend having a Brook-fieldviscosity of at least 1000 centipoises at 72 F. withsspindle No.4 and aspindle speed of 60 rpm.

16. A method of forming a stable suspension of medicinal pellets havinga predetermined rate of medicinal release over a predetermined delayedtime interval, said method comprising forming a homogeneous blend of anon-toxic compound which is liquid at room temperature and a non-toxiccompound which is solid at room temperature, mixing said pellets in saidblend at an elevated temperature and with agitation to disperse saidpellets in said blend in the form of a suspension, said blend having asubstantially lower viscosity at said elevated temperature than at alower temperature, said blend containing an amount of solid compound torender said suspension sufliciently viscous at said lower temperature tohold said pellets in suspension, reducing said elevated temperature ofsaid suspension to said lower temperature to thereby increase itsviscosity, said elevated temperature being not greater than the maximumtemperature which said pellets can withstand without deleteriouseffects, said suspension being agitated during said cooling step, i

17. A method of forming a stable suspension of medicinal pellets havinga predetermined rate of medicinal release over a predetermined delayedtime interval, said method comprising forming a homogeneous blend of apolyalkylene glycol which is liquid at room temperature and apolyalkylene glycol of greater molecular weight than said liquidpolyalkylene glycol and which is solid at room temperature, mixing saidpellets in said blend at an elevated temperature and with agitation todisperse said pellets in said blend, said blend having a substantiallylower viscosity at said elevated temperature than at a lowertemperature, said blend containing an amount of solid polyalkyleneglycol to render said suspension sufficiently viscous at said lowertemperature to hold said pellets in suspension, reducing said elevatedtemperature of said suspension to said lower temperature to therebyincrease its viscosity, said elevated temperature being not greater thanthe maximum temperature which said pellets can withstandwithoutdeleterious effects, said suspension being agitated during said coolingstep.

18. -A method according to claim 17, said polyalkylene glycolscomprising polyethylene glycols, said liquid poly ethylene glycol havingan average molecular weight between about 190 and 630 and a Sayboltviscosity at 210 -F.,'sec., ranging from about 38 to 66 and said solidpolyethylene glycol having an average molecular weight between about 950and 7500 and a Saybolt viscosity at 210 F., sec., ranging from about 85to 4200, the Brookfield viscosity of said blend at 72 F. with spindleNo. 4 and a spindle speed of rpm. being at least 1000 centipoises.

19. A method according to claim 17 said polyalkyl- -ene glycolscomprising polyethylene glycols, said liquid polyethylene glycol havingan average molecular weight of between about 380 and 420 and a Sayboltviscosity at 210 F., sec., from about 45 to 55 and said solidpolyethylene glycol having an average molecular weight of between about3000 and 3700 and a Saybolt viscosity at 210 F., sec., from about 350 to400, said blend comprising at least about 8% by weight of said solidpolyethylene glycol.

20. A method according to claim 17, said solid polyalkylene glycol beingmixed with said liquid polyalkylene glycol to form said homogeneousblend at a second elevated temperature at least as high as the meltingtemperature of said solid polyalkylene glycol, said method includingreducing the temperature of said blend from said sec ond elevatedtemperature to said first elevated temperature at which said pellets areadded thereto, said first elevated temperature being not substantiallygreater than 122 F References Cited in the file of this patent UNITEDSTATES PATENTS 2,471,358 Stephenson May 24, 1949 2,738,303 Blythe Mar.13, 1956 2,899,361 McMillion Aug. 11, 1959 2,928,770 Bardani Mar. 15,1960 2,975,099 Goyan et al. Mar. 14, 1961 FOREIGN PATENTS 789,844 GreatBritain Jan. 29, 1958

1. AN ENCAPSULTED, STABLE LIQUID SUSPENSION OF TIME RELEASE MEDICINALPELLETS HAVING A PREDETERMINED RATE OF MEDICINAL RELEASE OVER APREDETERMINED DELAY TIME INTERVAL, SAID PELLETS BEING DISPERSED ANDSUSPENDED INTO SUBSTANTIALLY MOISTURE-FREE, THICK, VISCOUS BUT FLOWABLELIQUID CARRIER IN WHICH SAID PELLETS ARE SUBSTANTIALLY INSOLUBLE, SAIDSUSPENSION BEING ENCAPSULATED IN A SOFT SHELL, HERMETICALLY SEALEDCAPSULE, SAID CARRIER BEING INERT WITH RESPECT TO SAID PELLETS AND SAIDCAPSULE AND COMPRISING A HOMOGENEOUS BLEND OF A NON-TOXIC COMPOUND WHICHIS LIQUID AT ROOM TEMPERATURE AND A NON-TOXIC THICKENING COMPOUND WHICHIS SOLID AT ROOM TEMPERATURE AND WHICH IS PRESENT IN AN AMOUNT TO RENDERTHE CARRIER SUFFICIENTLY VISCOUS TO HOLD SAID PELLETS IN SUSPENSION,SAID CARRIER BEING SUBSTANTIALLY INERT WITH RESPECT TO EFFECT ON SAIDPREDETERMINED RATE OF MEDICINAL RELEASE OF SAID PELLETS.